27 January 2009. Schizophrenia and bipolar disorder are diagnosed as distinct diseases, but do they share an underlying cause? That debate has gone on since Emil Kraepelin defined the two types of psychoses more than 100 years ago. Modern molecular genetics studies suggest shared origins (see SRF related news story; and see SRF related news story), but epidemiological work has yielded less consistent results.

New results from the largest family study to date could put that debate to rest. In a study of more than nine million Swedish people over 30 years, Paul Lichtenstein and colleagues at the Karolinska Institute in Stockholm, Sweden, find that first-degree relatives of people with schizophrenia are at higher risk for bipolar disorder, and vice versa. The work, published in the January 17 issue of the Lancet, shows a shared genetic risk for the two diseases, and adds to calls from some clinicians and researchers to rethink and revise the diagnostic distinction between the disorders (see SRF Live Discussion led by N. Craddock and M. Owen).

Lichtenstein, Christina Hultman, and collaborators had previously developed a linked database combining a multigeneration register of two million Swedish families and the public hospital records for all psychiatric inpatient admissions between 1973 and 2004 (Lichtenstein et al., 2006). They used this information to assess the risk of disease in first-degree relatives of 35,985 people treated for schizophrenia and 40,487 with bipolar disorder.

In agreement with the group’s previous results, first-degree relatives of people with schizophrenia had a nine times higher risk of getting the disease than unrelated control subjects. They also showed an increased risk among half-siblings, though it was not as large as full siblings (3.6 times for maternal and 2.7 times for paternal half-siblings, respectively). The data also included adopted families, where there was an increased risk of disease for adopted children whose biological parent had schizophrenia, or for siblings adopted into different families where one had the disease.

For bipolar disorder, a similar pattern emerged. The risk for first-degree relatives was elevated nearly eight times. Half-siblings and adopted children showed a lower, but still elevated risk, similar to that seen in the schizophrenia cohort.

The elevated risk cut across disorders. Siblings of subjects with schizophrenia had nearly a four times higher risk of bipolar disorder, and vice versa. The risk carried over in adopted children where a biological parent was affected, and in siblings separated by adoption. Half-siblings showed a variable low elevation in risk that was mostly not statistically significant.

From these results, the investigators calculated the genetic contribution to schizophrenia (heritability) at 64 percent and 59 percent for bipolar disorders. The correlation of genetic risk for the two disorders was 0.60, a number that indicates a large part, but not all, of the genetic risk for the disorders is shared. “Thus, some genes are probably associated with the risk for both disorders, and some with the risk for only one disorder,” the authors write. “This possibility should be considered in future research and clinical studies.”

“These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities,” the authors conclude.

That view is echoed in an accompanying editorial from Michael Owen and Nick Craddock of Cardiff University, United Kingdom. “We now must ask whether clinical practice and research can continue to be best served by persistence in basing our diagnoses on the binary concept,” they write. The answer to that question raises another: If the Kraepelinian dichotomy is abandoned, they ask, with what should it be replaced? Owen and Craddock advocate new diagnostic criteria that detail and carefully measure key domains of psychopathology. The question is timely, they say, because the next editions of both major diagnostic manuals, the DSM-V (Diagnostic and Statistical Manual of Mental Disorders) and ICD11 (International Classification of Diseases and Related Health Problems) are in development now.—Pat McCaffrey.

This is a very interesting analysis and the largest and most definitive study to date. The results make clear that

1. some genetic effects are shared between BPD and schizophrenia;
2. some genetic effects are unique;
3. some environmental effects are shared;
4. some environmental effects are unique.

What is not known is which G or E effects validate diagnostic class. And whether all the effects are small, and apply to subgroups, and, therefore, may be more useful in resolving syndrome status than suggesting BPD and schizophrenia are one disease. The one-disease-or-two debate only has meaning if there are two diseases at most. More likely, we have two syndromes with some overlapping subjects, some overlapping psychopathology, some overlapping phenotypes.

The key question is whether to have the two syndromes as the unit of analysis for most studies. This can lead to new information on unique and shared effects, but the heterogeneity of the syndromes will confound this approach.

An alternative approach is the "domains of pathology" approach, which presumes that shared features related to psychopathology common in both syndromes (e.g., depression, reality distortion, cognition impairment) and unique features may relate to psychopathology usually not shared across the syndromes (e.g., avolition in schizophrenia, episodic mood pattern in BPD, differential developmental pathways, overall illness pattern, phenomenology of thought disorder). Domains of pathology also permit within syndrome studies (e.g., BPD with and without psychosis, deficit versus non-deficit schizophrenia).

The results of the family/adoption study by Lichtenstein et al. (2009) and our twin study (Cardno et al., 2002) are remarkably similar. Using a non-hierarchical diagnostic approach, the genetic correlation between schizophrenia and bipolar/mania was 0.60 in the family/twin study and 0.68 in the twin study. The heritability estimates were somewhat lower in the family/adoption (~60 percent) than twin study (~80 percent), but can still be said to be substantial and similar for both disorders.

When we adopted a hierarchical approach, with schizophrenia above mania, we found no monozygotic twin pairs where one twin had schizophrenia and the other had bipolar/mania, but with their considerably larger sample, Lichtenstein et al. (2009) were able to confirm a significantly elevated risk for bipolar disorder in siblings of probands with schizophrenia (RR = 2.7), even when individuals with co-occurrence of both disorders were excluded.

I think there is a potentially interesting link between the family/adoption and twin studies focusing mainly on non-hierarchical diagnoses: Owen and Craddock’s (2009) commentary on the family/adoption study, where they advocate a dimensional approach, and Will Carpenter’s SRF comment regarding the value of domains of psychopathology. The non-hierarchical approach (where individuals can have a diagnosis of both schizophrenia and bipolar disorder during their lifetime) could be viewed as a form of dimensional/domains of psychopathology approach, with schizophrenia and bipolar disorder each having a dimension of liability, and there is now evidence from family, twin, and adoption analyses that these dimensions are correlated, i.e., that there is some overlap in etiological influences.

If schizophrenia and bipolar disorder share some causal factors in common, what might be the implications for the unresolved status of schizoaffective disorder? Our twin study suggested that the genetic (but not environmental) liability to schizoaffective disorder is entirely shared with schizophrenia and mania, defined non-hierarchically (Cardno et al., 2002). If so, and if schizophrenia and bipolar disorder share some genetic susceptibility loci in common, while other loci are not shared, then risk of schizoaffective disorder (or perhaps the bipolar subtype) could be elevated either by the coincidental co-occurrence of non-shared susceptibility loci, or by the occurrence of loci that are common to both disorders.

In this case, any loci that influence risk of schizoaffective disorder (bipolar subtype?) should also increase risk of schizophrenia and/or bipolar disorder, and this model would be refuted if any relatively specific susceptibility loci for schizoaffective disorder were confidently identified.

Some further outstanding issues:

The relative usefulness of: 1) a hierarchical versus non-hierarchical approach to diagnosis of schizoaffective disorder (and if hierarchical, which one?); 2) the various definitions of schizoaffective disorder; 3) schizoaffective disorder per se compared with its subtypes.

Also, to what extent do environmental risk factors for schizophrenia, bipolar disorder, and schizoaffective disorder have different relationships from genetic risk factors?